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Interleukin 28 Is a Potential Therapeutic Target for Sepsis

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Interleukin 28 Is a Potential Therapeutic Target for Sepsis Clinical Immunology 205 (2019) 29–34 Contents lists available at ScienceDirect Clinical Immunology journal homepage: www.elsevier.com/locate/yclim Interleukin 28 is a potential therapeutic target for sepsis T ⁎ Qin Luoa,b, Yi Liuc, Shuang Liub, Yibing Yinb, Banglao Xud, Ju Caoa, a Department of Laboratory Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China b Key Laboratory of Diagnostic Medicine designated by the Ministry of Education, Chongqing Medical University, Chongqing, China c Department of Intensive Care Unit, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China d Department of Laboratory Medicine, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, China ARTICLE INFO ABSTRACT Keywords: Identification of new therapeutic targets for the treatment of sepsis is imperative. We report here that cytokine Interleukin-28 IL-28 (IFN-λ) levels were elevated in clinical and experimental sepsis. Neutralization of IL-28 protected mice Sepsis from lethal sepsis induced by cecal ligation and puncture (CLP), which was associated with improved bacterial Infection clearance and enhanced neutrophil infiltration. Conversely, administration of recombinant IL-28 aggravated Immunity mortality, facilitated bacterial dissimilation and limited neutrophil recruitment, in the model of sepsis induced Neutrophil by CLP. This study defines IL-28 as a detrimental mediator during sepsis and identifies a potential therapeutic target for the immune therapy in sepsis. 1. Introduction immunopathology of sepsis is still poorly understood. To address this issue, we examined the potential role of IL-28 in the Each year, about 31.5 million individuals develop sepsis, and up to progression of sepsis. Blood specimens from patients with sepsis de- 5.3 million deaths due to sepsis occur worldwide [1]. The current monstrated increased release of IL-28A. We used the cecal ligation and treatment of sepsis relies on the administration of antibiotics and organ puncture (CLP) model of sepsis to test effects of IL-28 on sepsis. function support, and there is no specific therapeutic agent approved Neutralization of IL-28 reduced CLP-induced sepsis mortality, while IL- for the treatment of sepsis [2]. In sepsis, the host immune response 28 administration in sepsis increased mortality. This study identifies triggered by an invading pathogen fails to return to homeostasis, re- cytokine IL-28 as a new immunotherapeutic agent for the treatment of sulting in aberrant inflammation and immune suppression, and septic sepsis. patients fail to eradicate primary infections and are susceptible to secondary, mostly opportunistic, infections [3]. Identification of the 2. Materials and methods immune factors involved in sepsis-induced aberrant inflammation and immune suppression will provide novel potential targets for in- 2.1. Study subjects and data collection dividualized immune therapy in the patients with sepsis. The classical IFN family cytokines, such as types I and II IFNs, have Patients who met the clinical criteria for sepsis-3 were screened for been shown to play an important role in regulating host immune re- eligibility within the first 24 h after they were admitted to the Intensive sponses during sepsis [4]. Type III IFNs, or IFN-λs, are a newly de- Care Unit of The Second Affiliated Hospital of Chongqing Medical scribed member of the IFN family, and they consist of three members in University between September 2015 and December 2017 [8]. A total of humans, denoted IL-28A (IFN-λ2), IL-28B (IFN-λ3), and IL-29 (IFN-λ1), 46 septic patients were enrolled. Patient data such as Acute Physiology and two members in mice (IL-28A and IL-28B) [4]. IFN-λs signal and Chronic Health Evaluation II (APACHE II) score, Sequential Organ through a heterodimeric receptor consisting of the IL-28 receptor (IL- Failure Assessment (SOFA) score, the counts of white blood cells (WBC) 28R) and IL-10RB, which is expressed predominantly on mucosal sur- and the levels of C-reaction proteins (CRP), microbial culture results, faces and on neutrophils [5,6]. IL-28 cytokine family members could be the length of ICU stay and hospital stay, and the outcome of ICU stay produced by various cells upon viral infection or Toll like receptor li- were recorded. Patients with malignancy, organ transplantation, HIV- gation [7]. Although the antiviral and anti-tumor activity has been infected patients, and patients receiving immunosuppressive agents in extensively studied during the past decade, the role of IL-28 in the the past 8 weeks were excluded from the study. 26 healthy donors with ⁎ Corresponding author at: Department of Laboratory Medicine, The First Affiliated Hospital of Chongqing Medical University, Yuzhong District, Chongqing, China. E-mail address: [email protected] (J. Cao). https://doi.org/10.1016/j.clim.2019.05.012 Received 23 April 2019; Received in revised form 17 May 2019; Accepted 17 May 2019 Available online 20 May 2019 1521-6616/ © 2019 Elsevier Inc. All rights reserved. Q. Luo, et al. Clinical Immunology 205 (2019) 29–34 Table 1 no medical problems in the medical examination center of The First Baseline characteristics of patients with sepsis and healthy controls. Affiliated Hospital of Chongqing Medical University were also included Characteristics Sepsis patients Healthy controls as controls. This protocol was approved by the Clinical Research Ethics (n = 46) (n = 26) Committee of Chongqing Medical University, and informed consent was obtained from all participants according to the Declaration of Helsinki. Male sex 22 11 Age, years 55 (45–71) 49 (40–65) 9 WBC, 10 /L 9 (6–19) 6 (4–9) 2.2. Sepsis model CRP, mg/L 120 (30–216) NA Infection site, no. of patients Respiratory 17 NA Cecal ligation puncture (CLP) was used as a model of sepsis as de- Abdominal 16 NA scribed in our previous studies [9,10]. Briefly, C57BL/6 mice were Vascular 3 NA anesthetized intraperitoneally (i.p.) with a mixture of xylazine (4.5 mg/ Urinary 5 NA kg) and ketamine (90 mg/kg), and the cecum was exposed, ligatured at Other 5 NA its external third, and punctured through with a 21-gauge needle. The Bacteremia 30 NA Isolates, no. of patients cecum was then returned to the peritoneal cavity, and incisions were Gram positive 12 NA closed. Sham-operated (control) animals underwent identical lapar- Gram negative 22 NA atomy, and the cecum was exposed but not ligated or punctured and Fungus 1 NA was then replaced in the peritoneal cavity. Mice received saline (5 ml Miscellaneous 6 NA Unknown 5 NA per 100 g body weight) subcutaneously for resuscitation. Survival was APACHE II score 16.2 (13.1–22.5) NA monitored twice daily for 14 d. All experiments involving animals ad- SOFA score 8.2 (5.1–15.5) NA hered to guidelines and received the approval of the Institutional Re- – ICU stay, days 11 (3 19) NA view Committee for Animal Care and Use at Chongqing Medical Uni- Died/survived 6/40 NA versity. NOTE. Data are expressed as median (interquartile range) unless otherwise indicated. APACHE II: acute physiology and chronic health evaluation II; SOFA: 2.3. Measurement of IL-28 sequential organ failure assessment; ICU: intensive care unit; WBC: white blood cells; CRP: C-reaction protein; NA: not applicable. IL-28 cytokines were quantified using specific ELISA kits, following the manufacturer's instructions. Mouse IL-28A/B kits were from R&D Systems, and human IL-28A (cross-reacting with IL-28B) kits were also from R&D Systems. Fig. 1. IL-28 protein levels were elevated in clinical and experimental sepsis (A) IL-28A concentrations were measured by ELISA in serum samples collected from 46 patients with sepsis (40 survivors and 6 non-survivors) and from 26 healthy control subjects. Horizontal bars represent median values, and dots represent individual participants. *p < .05, compared between groups (denoted by horizontal bracket; Kruskal-Wallis test followed by Dunn's multiple comparisons post test). (B) Local and systemic IL-28 production in mice after cecal ligation puncture (CLP)–induced sepsis. C57BL/6 mice (n = 6 per group) were subjected to sham or CLP. Organs were removed at the indicated time points, blood was collected by cardiac puncture, and peritoneal lavage fluid (PLF) was obtained by washing the peritoneal cavity with 5 ml of sterile PBS. Samples were assayed for IL-28 content by ELISA. *p < .05, **p < .01,***p < .001, compared with sham control mice (Mann–Whitney U test). 30 Q. Luo, et al. Clinical Immunology 205 (2019) 29–34 2.7. Determination of bacterial load Serial dilutions of blood and peritoneal lavage fluid (PLF) were prepared in sterile PBS for plating on brain-heart-infusion agar plates. Colony- forming unit (CFU) counts were then determined after 24-hour culture. 2.8. Statistical analysis Human data were expressed as scatter dot plots with medians. Mice data were expressed as box-and-whisker plots showing the smallest observation, lower quartile, median, upper quartile, and largest ob- servation or as medians with interquartile ranges. Comparisons be- tween groups were tested using the Mann-Whitney U test or Kruskal- Wallis test followed by Dunn's multiple comparisons post test as ap- propriate. For survival studies, Kaplan-Meier analyses followed by log- rank tests were performed. All analyses were done using GraphPad Prism version 5.01 (GraphPad Software, San Diego, CA). p values < .05 were considered statistically significant. Fig. 2. Neutralization of IL-28 activity with monoclonal antibody attenuated 3. Results CLP-induced sepsis. C57BL/6 mice were subjected to CLP, 10 μg of anti-mouse IL-28A/B neutralizing monoclonal antibody was administered intraperitoneally 3.1. The levels of IL-28 were up-regulated in human and murine sepsis in 50 μl of PBS at 2 h after CLP, followed by a booster dose of 10 μg at 8 h later after CLP.
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